title: Betulinic acid and betulin ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro.
abstract: Ethanol consumption leads to many kinds of liver injury and suppresses innate immunity, but the molecular mechanisms have not been fully delineated. The present study was conducted to determine whether betulinic acid (BA) or betulin (BT) would ameliorate acute ethanol-induced fatty liver in mice, and to characterize whether Toll like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) were involved in ethanol-stimulated hepatic stellate cells (HSCs). EtOH (5mg/kg) and BA or BT (20 or 50mg/kg) were applied in vivo, while EtOH (50mM) and BA or BT (12.5 or 25μM) were applied in vitro. Administration of BA or BT significantly prevented the increases of serum ALT and AST caused by ethanol, as well as serum TG. Supplement of BA or BT prevented ethanol-induced acidophilic necrosis, increased hepatocyte nuclei and stromal inflammation infiltration as indicated by liver histopathological studies. Administration of BA or BT significantly decreased CYP2E1 activities and expression of SREBP-1caused by ethanol, however, lower dosage of BA or BT showed slight effects on CYP2E1 activity or expression of SREBP-1c. BA or BT administration significantly decreased the expression of TLR4, and increased the phosphorylation of STAT3. In vitro, BA or BT treatment reduced the expressions of α-SMA and collagen-I in ethanol-stimulated HSCs via regulation of TLR4 and STAT3, coincided with in vivo. All of these findings demonstrated that BA or BT might ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro, promising agents for ethanol-induced fatty liver therapies.
authors.affiliation: College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wan
authors.forename: Shuang
authors.initials: S
authors.lastname: Jiang
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Lian
authors.forename: Ting
authors.initials: T
authors.lastname: Bai
authors.forename: Peng-He
authors.initials: PH
authors.lastname: Cui
authors.forename: Xiao-Ting
authors.initials: XT
authors.lastname: Sun
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Jin
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Wu
authors.forename: Ji-Xing
authors.initials: JX
authors.lastname: Nan
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002460:Cell Line; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D014315:Triterpenes / Q000008:administration & dosage*; D000094062:Betulinic Acid
chemical_list: D008070:Lipopolysaccharides; D053978:Pentacyclic Triterpenes; D050796:STAT3 Transcription Factor; D051780:Sterol Regulatory Element Binding Protein 1; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D014315:Triterpenes; C002503:betulin; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000094062:Betulinic Acid
keywords: ALT; AST; BA; BT; Betulin; Betulinic acid; CYP2E1; Ethanol; HSCs; LPS; SREBP-1c; STAT3; TG; TLR4; Toll-like receptor4; alanine aminotransferase; aspartate aminotransferase; betulin; betulinic acid; cytochrome P4502E1; hepatic stellate cells; lipopolysaccharide; serum triglyceride; signal transducer and activator of transcription 3; sterol regulatory element-binding protein-1c; α-SMA; α-smooth muscle actin